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BACKGROUND: Recently, the Aldara-induced psoriasis-like skin inflammation model in mice has attracted increased attention, due to its dependence of the same immunological pathways and cell types as in human psoriasis.OBJECTIVES: To study the impact of constitutive deficiency of tumour necrosis factor α (TNFα) and its upstream regulator MAPKAPK-2 (MK2) in the Aldara-induced psoriasis-like skin inflammation model.METHODS: TNFα knockout (KO), MK2 KO and wild-type mice divided into separate groups received either 45 mg Aldara cream or control cream for five consecutive days. The skin inflammation was evaluated clinically, histologically, and by RT-qPCR.RESULTS: We found that TNFα KO mice developed significantly less skin inflammation compared with wild-type mice, as evaluated clinically and histologically. At the molecular level, we demonstrated that the Aldara-induced mRNA expression of the psoriasis-related inflammatory markers IL-17C, IL-23p19, IL-12p40, IL-17A, IL-22 and S100A8 was significantly decreased in TNFα KO mice compared with wild-type mice. No significant difference in the mRNA expression of these inflammatory markers between MK2 KO mice and wild-type mice was found, although Aldara-treated MK2 KO mice revealed a tendency towards a lower mRNA expression of IL-17A and IL-22 compared with wild-type mice.CONCLUSION: We were able to demonstrate significantly lower level of inflammation in TNFα KO mice compared with wild-type mice, supporting the use of this model in future studies characterizing the role of TNFα in psoriasis. This article is protected by copyright. All rights reserved.

BACKGROUND: Cadherin switch in melanoma, with loss of E-cadherin and up-regulation of N-cadherin, is believed to underlie melanoma cell detachment from the epidermis and promotion of dermal and vascular melanoma invasion. The tumour suppressor PTEN has been suggested as a potential regulator of this cadherin switch. OBJECTIVES: To study the biological and clinical implications of cadherin switch and PTEN expression in melanoma progression. METHODS: We constructed tissue microarrays from primary tumour samples from 393 formalin-fixed paraffin-embedded melanomas diagnosed between 2001 and 2006. Median follow-up was ten years. Tissue microarray sections were stained by immunohistochemistry for E-cadherin, N-cadherin, and PTEN, and expression was analysed semi-quantitatively. RESULTS: Breslow thickness correlated strongly with reduced/absent PTEN expression (p

Udgivelsesdato: 2010-Dec BACKGROUND: Anti-TNFα therapies are well established for severe psoriasis; however, their mechanism of action in disease resolution is not fully understood. p38 mitogen-activated protein kinase (MAPK) is a kinase known to play a key role in the pathogenesis of psoriasis. OBJECTIVES: To elucidate the early effects of adalimumab, a human monoclonal anti-TNFα antibody, on the expression of interleukins in psoriatic skin. PATIENTS AND METHODS: Biopsies from patients with psoriasis were examined before and after the start of adalimumab therapy. mRNA expression of cytokines were measured with quantitative polymerase chain reaction. p38 MAPK and signal transducer and activator of transcription 3 (STAT3) were analysed by Western blotting and immunofluorescence analyses, and IL-17A and IL-17C were examined with immunohistochemistry. RESULTS: The increased mRNA level of IL-1β, IL-8, IL-17C and IL-20 in lesional psoriatic skin was already significantly reduced 4 days after the start of adalimumab treatment, i.e. before clinical and histological improvement was detectable. The mRNA expression of the Th17-derived cytokines IL-17A, IL-17F and IL-22 as well as the dendritic cell product IL-23/IL-12 (p40) were not significantly reduced until 2 weeks after the start of treatment, whereas the mRNA expression of IL-23 (p19) and the Th1 cytokines IFN-γ and IL-2 were reduced late in disease resolution. IL-1β, IL-8 and IL-20 are all known to be regulated by p38 MAPK. IL-17C was produced by cultured human keratinocytes and this production was also mediated by a p38 MAPK dependent mechanism. Moreover, the early effects of adalimumab included the phosphorylation of p38 MAPK, but not STAT3 phosphorylation. CONCLUSIONS: This study indicates that an important mechanism of action of anti-TNFα therapy in psoriasis is a reduction in p38 MAPK phosphorylation and a subsequent decrease in the expression of p38 MAPK regulated genes.

In the period February 1994 to November 1995 11 laparoscopic adrenalectomies were performed at our institution (seven women, four men). A transperitoneal approach was used in both right- and left-sided operations. Results were collected retrospectively. Indications for surgery were: Conn's syndrome (four), Cushing's syndrome (two), phaecromocytoma (four), and incidentaloma (one). The operations took median 170 minutes (range 105-250 minutes). Median size of the tumour was 4 cm range 1(1/2)-5 cm). No significant peri- or postoperative complications were recorded. The patients were discharged from the surgical unit median two days after surgery. Laparoscopic operation emerges as an alternative to open operation when dealing with smaller adrenal tumours. Because of the small number of patients, these operations have to be restricted to a few centres where both internists, anaesthesiologists and surgeons with expertise in this field are found.

Iliac bone biopsies from 69 patients (48 females, 21 males; median age 58 years; range 17-79 years) with primary hyperparathyroidism (PHP) were examined, and static histomorphometric parameters compared to 30 age- and sex-matched normal controls. The control group for the dynamic parameters constituted 20 sex-matched younger normal controls. Fractional volume of trabecular bone was normal, but the trabeculae were thinner (p less than 0.05) in PHP. The structural parameters marrow space star volume, intertrabecular distance, and mean trabecular plate density were not significantly different in PHP patients compared to normal controls, but the age-related increase, for females, in marrow space star volume and decrease, for both sexes, in mean plate density observed in the controls were not noticed in the PHP group. Trabecular bone remodeling was found significantly increased in the PHP patients reflected by increased extension of eroded (p less than 0.001), osteoid (p less than 0.001), and labeled surfaces (p less than 0.05). The activation frequency was increased by approximately 50% (p less than 0.001). Neither PHP patients nor controls showed age-related decrease in trabecular thickness, and accordingly in both groups the bone balance per remodeling cycle was very close to and not significantly different from zero. Normal postmenopausal women (age greater than or equal to 50 yr) had lower trabecular bone volume (p less than 0.001) and higher intertrabecular distance than normal pre-menopausal women (age less than 50 yr).(ABSTRACT TRUNCATED AT 250 WORDS)